Chapter 253

## Abstract

Abstract

1. Campomelic dysplasia (CD) is a rare, dominant, and usually neonatal lethal chondrodysplasia clinically and radiologically defined by a number of skeletal and extraskeletal phenotypes, the most conspicuous of which is angulation of the long bones. Bent or bowed limbs occur in other skeletal malformation syndromes and are not pathognomonic for CD. Major diagnostic radiologic features include bowed or angulated femora and tibiae, hypoplastic scapulae, vertically narrow iliac wings, and nonmineralized thoracic pedicles. No single feature is diagnostic, but each of these appears with high frequency, and no other syndrome has this combination of features. Additional common radiologic features are facial hypoplasia, abnormal cervical vertebrae, slender ribs, 11 pairs of ribs, small chest, dislocated hips, a variety of pelvic abnormalities, and short first metacarpal. Common clinical features include micrognathia, respiratory distress, flat nasal bridge, pretibial dimples, macrocephaly, and talipes equinovarus.

2. More than two-thirds of 46,XY campomelic dysplasia patients are sex reversed, developing as phenotypic females due to a failure to form testes. The degree of sex reversal can vary, with the most common outcome being normal phenotypic female with dysgenic ovaries.

3. Dominant mutations in the transcription factor SOX9 are responsible for both the skeletal and the sex development phenotypes. Mutation analysis and functional assays suggest that the phenotypes result from haploinsufficiency due to loss-of-function mutations of a single SOX9 allele. SOX9 mutations apparently do not cause sex reversal in the absence of CD skeletal defects.

4. SOX9 appears to be a critical component of the developmental pathways of both cartilage formation and testis formation, functioning independently in the development of these two dissimilar tissues. SOX9 mutations cause a loss of protein function that leads to a failure to propagate the appropriate developmental signals in both chondrogenic tissue and the indifferent gonad.

5. Expression of SOX9 is the earliest marker of cartilage differentiation and is required for cartilage formation. The SOX9 protein is expressed during embryonic chondrogenesis and directly regulates type II collagen gene expression in chondrocytes. SOX9 may also be directly involved in regulation of type XI collagen, which is coexpressed with type II collagen, both collagens being essential for normal cartilage development and skeletal morphogenesis. In chimeric mice, cells with homozygous deletions of Sox9 are excluded from all cartilages and do not express chondrocyte-specific markers, showing the essential role of Sox9 in chondrogenesis and cartilage formation.

6. During mouse gonadal development, Sox9 is expressed in both XX and XY embryos in the undifferentiated genital ridge. In XY embryos, Sox9 is up-regulated coincident with the onset of expression of Sry, the Y chromosome testis determination factor, and continues to be expressed at high levels in developing testes, with expression limited to the Sertoli cells. At the corresponding time in XX embryos, Sox9 expression is down-regulated. This is the earliest difference in gene expression known between males and females other than that of Sry itself. SOX9 appears to act as a partner of SF1 in activating the Sertoli cell-specific expression of anti-Müllerian hormone (AMH), a hormone that promotes regression of the Müllerian ducts, the primordia of female-specific sex organs. The timing and sexually dimorphic expression of Sox9 in differentiating gonads, and its involvement in transactivation of a testis-specific gene, suggests a critical role for SOX9 in testis determination.

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